人聚（ADP - 核糖）聚合酶1酶 - 底物复合物的建模

Modeling of the Enzyme-Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1.

作者信息

Nilov D K, Pushkarev S V, Gushchina I V, Manasaryan G A, Kirsanov K I, Švedas V K

机构信息

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.

Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, 119991, Russia.

出版信息

Biochemistry (Mosc). 2020 Jan;85(1):99-107. doi: 10.1134/S0006297920010095.

DOI:10.1134/S0006297920010095

PMID:32079521

Abstract

Poly(ADP-ribose) polymerase 1 (PARP-1) is a key DNA repair enzyme and an important target in cancer treatment. Conventional methods of studying the reaction mechanism of PARP-1 have limitations because of the complex structure of PARP-1 substrates; however, the necessary data can be obtained by molecular modeling. In this work, a molecular dynamics model for the PARP-1 enzyme-substrate complex containing NAD+ molecule and the end of the poly(ADP-ribose) chain in the form of ADP molecule was obtained for the first time. Interactions with the active site residues have been characterized where Gly863, Lys903, Glu988 play a crucial role, and the S1-like mechanism for the enzymatic ADP-ribosylation reaction has been proposed. Models of PARP-1 complexes with more sophisticated two-unit fragments of the growing polymer chain as well as competitive inhibitors 3-aminobenzamide and 7-methylguanine have been obtained by molecular docking.

摘要

聚（ADP - 核糖）聚合酶1（PARP - 1）是一种关键的DNA修复酶，也是癌症治疗中的一个重要靶点。由于PARP - 1底物结构复杂，传统研究PARP - 1反应机制的方法存在局限性；然而，通过分子建模可以获得必要的数据。在这项工作中，首次获得了包含NAD + 分子和以ADP分子形式存在的聚（ADP - 核糖）链末端的PARP - 1酶 - 底物复合物的分子动力学模型。已对与活性位点残基的相互作用进行了表征，其中Gly863、Lys903、Glu988起着关键作用，并提出了酶促ADP - 核糖基化反应的S1样机制。通过分子对接获得了PARP - 1与生长聚合物链更复杂的二聚体片段以及竞争性抑制剂3 - 氨基苯甲酰胺和7 - 甲基鸟嘌呤的复合物模型。